Thiazolidinediones, TZDs (also known as glitazones) reverse insulin resistance in type 2 diabetes and potentially offer comprehensive treatment of the disease. Black box warnings on the labels of rosiglitazone (Avandia®) and pioglitazone (Actos®), the two currently marketed drugs in the class, were required by the FDA in August 2007 to alert the medical community to a risk heart failure. In accordance with the required warning, patients should be observed carefully for signs and symptoms of heart failure, including excessive, rapid weight gain, dyspnea, and/or edema. Furthermore, the thiazolidinediones are contraindicated in advanced congestive heart failure.
Currently, the development of thiazolidinedione side effects is unpredictable and potentially injurious to the patient, which discourages patient compliance and disrupts healthcare delivery. Such uncertainties burden medical management and increase healthcare costs. Much of the mechanistic insight into the metabolic and cardiovascular side effects of these drugs has been learned from animal studies. There is an urgent need to garner scientific evidence from human clinical studies to prioritize the use of thiazolidinediones.
Thiazolidinedione therapy induces a mean weight gain of 4 to 5 kg, and doubles or triples the risk of edema. Weight gain exacerbates the diabetic condition itself and may be the result of adiposity, fluid retention, or a combination of the two. Peroxisome proliferator-activated receptor (PPARG) agonists such as the thiazolidinediones contribute to adiposity through adipogenesis and increased fat accretion. Microcirculatory dysregulation and vascular permeability are already present in diabetes. PPAR gamma type receptor agonists as a class may promote edema through fluid retention due to renal sodium reabsorption and increased adipose tissue vascular permeability. Effects may also be drug specific.
Physiogenomics is a medical application of sensitivity analysis and systems engineering that defines a new paradigm in the genetic analysis of complex human phenotypes. Sensitivity analysis is the study of the dependence of a system on changes in its components. In physiogenomics, single nucleotide polymorphisms (SNPs), for example, provide the variable components of genes, and analysis of the relationship between that variation and the physiological response provides information about which genes play important roles in the physiological process. This approach has been advanced in human clinical studies and in animal models. The associated gene markers are combined into SNP ensembles harnessing their combined predictive power to estimate functional variability among individuals similarly treated.
By testing broad hypotheses about mechanistic features of drug effects, physiogenomics can generate novel hypotheses in relation to mechanisms of drug safety. Needed are improvements in the understanding of the weight and edema profiles of patients treated with rosiglitazone or pioglitazone.